The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination
The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination
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DOI：
10.1038/nature01802
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发表时间：
2003-08-14
期刊：
影响因子：
64.8
通讯作者：
Courtois, G
中科院分区：
文献类型：
--
作者：
Kovalenko, A;Chable-Bessia, C;Courtois, G
NF-kappaB 转录因子在炎症、免疫反应、肿瘤发生和细胞凋亡保护中发挥关键作用 (1,2)。在大多数细胞中，这些因子通过与 IkappaB 抑制剂结合而在细胞质中保持失活。在各种试剂刺激后，IkappaB 被 IkappaB 激酶 (IKK) 复合物 (3) 磷酸化并被蛋白酶体降解，从而使 NF-kappaB 易位到细胞核并激活其靶基因。在此，我们报道 CYLD（一种在家族性圆柱瘤病中发生突变的肿瘤抑制因子）(4) 与 IKK5,6 的调节亚基 NEMO 相互作用。 CYLD 还与肿瘤坏死因子受体 (TNFR) 相关因子 2 (TRAF2) 直接相互作用，TRAF2 是一种接头分子，参与 TNF/神经生长因子受体家族成员的信号传导。 CYLD 具有针对非 K48 连接的多聚泛素链的去泛素化活性，并负向调节 TRAF 介导的 IKK 激活，强化了泛素化参与 TRAF 激活 IKK 的观点，并表明 CYLD 在此过程中发挥作用。在圆柱瘤病中发现的 CYLD 截短导致酶活性降低，表明 CYLD 底物去泛素化受损与人类病理生理学之间存在联系。
NF-kappaB transcription factors have key roles in inflammation, immune response, oncogenesis and protection against apoptosis (1,2). In most cells, these factors are kept inactive in the cytoplasm through association with IkappaB inhibitors. After stimulation by various reagents, IkappaB is phosphorylated by the IkappaB kinase (IKK) complex(3) and degraded by the proteasome, allowing NF-kappaB to translocate to the nucleus and activate its target genes. Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis(4), interacts with NEMO, the regulatory subunit of IKK5,6. CYLD also interacts directly with tumour-necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), an adaptor molecule involved in signalling by members of the family of TNF/ nerve growth factor receptors. CYLD has deubiquitinating activity that is directed towards non-K48-linked polyubiquitin chains, and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process. Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology.